Is it more effective for anhedonia and avolition? A systematic review and meta‐analysis of non‐invasive brain stimulation interventions for negative symptoms in schizophrenia

Abstract Background Noninvasive brain stimulation (NIBS) techniques are a promising tool for treating the negative symptoms of schizophrenia. Growing evidence suggests that different dimensions of negative symptoms have partly distinct underlying pathophysiological mechanisms. Previous randomized controlled trials (RCTs) have shown inconsistent impacts of NIBS across dimensions. Objective This systematic review and meta‐analysis evaluated the effects of NIBS on general negative symptoms, and on specific domains, including blunted affect, alogia, asociality, anhedonia, and avolition. Data Sources
 PubMed, Web of Science, Embase, Cochrane CENTRAL, PsycINFO, OpenGrey, and Clinicaltrials.gov from the first date available to October, 2023. Results Among 1049 studies, we identified eight high‐quality RCTs. NIBS significantly affects general negative symptoms (SMD = −0.54, 95% CI [−0.88, −0.21]) and all five domains (SMD = −0.32 to −0.63). Among dimensions, better effects have been shown for improvement of avolition (SMD = −0.47, 95% CI [−0.81, −0.13]) and anhedonia (SMD = −0.63, 95% CI [−0.98, −0.28]). Subgroup analyses of studies that applied once daily stimulation or >10 sessions showed significantly reduced negative symptom severity. Conclusion NIBS exerts distinct effects across multiple dimensions of negative symptom, with treatment effects related to stimulation frequency and total sessions. These results need to be confirmed in dedicated studies.

6][7][8] Several meta-analyses investigating NIBS for improving negative symptoms have consistently demonstrated that patients receiving active stimulation show significantly better effects compared with sham groups, with average effect sizes ranging from 0.31 to 0.61. 7,9,109][20] Our understanding of the pathophysiology of diminished expression (blunted affect and alogia) is less well developed and has focused on three main areas: emotion expression deficits, dysfunction in emotion perception, and insufficient cognitive resources for speech production. 16,17,21[24] Previous randomized controlled trials (RCTs) have shown that NIBS impacts each of these negative symptom dimensions differently. 25,26When Kumar and colleagues 27 applied 20 Hz rTMS to the DLPFC of patients with schizophrenia, the rTMS group had significantly lower anhedonia, alogia, and attention impairment subscale scores compared with the sham group.In Gan's study, patients treated with 10 Hz rTMS show significant improvements in effective flattening and anhedonia. 28Palm and colleagues 29 did not find significantly improve anhedonia in patients with schizophrenia after 2 mA tDCS treatment.However, these studies varied in subjects, stimulus parameters, stimulus techniques, results, and other factors.Thus, whether NIBS is effective across negative symptom dimensions, and whether its effectiveness varies by dimension, is currently unknown.
This systematic review and meta-analysis addresses the growing evidence that negative symptom dimensions have partly distinct underlying pathophysiological mechanisms, including from previous RCTs showing that NIBS impacts these dimensions differently.
Current meta-analyses in this field have focused on overall negative symptom improvements, neglecting dimension-specific differences. 7,9,10Thus, we conducted a meta-analysis of eight studies to examine the effects of NIBS on schizophrenia's negative symptoms with subgroup analyses.

| ME THODS
The methods are based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (see Table S1). 30o authors (Chen, Y. & Li, Z.) independently conducted the literature search, study selection, data extraction, and quality assessment.Disagreements were resolved by consensus, following joint examination of the studies.No registration information or review protocol for this review.

| Literature search
We conducted a comprehensive literature search using online databases PubMed, Web of Science, Embase, Cochrane CENTRAL, PsycINFO, OpenGrey, and Clini caltr ials.gov, up to October 2023.We used the following search term strategy: non-invasive brain stimulation AND negative symptoms AND schizophrenia.A detailed description of keywords and search results is available in Table S2.
Reference lists of related articles and reviews were also screened.
There was no restriction on publication date.

| Study selection
All searched studies were imported into the Zotero software for screening.Subsequently, duplicate articles were removed and unpublished studies were excluded.For non-English articles, we read the English abstracts or used a translator.The inclusion criteria for the current meta-analysis were as follows: (1) RCTs; (2) studies that used NIBS to treat patients with schizophrenia; (3) trials with a minimum duration of one intervention week; and (4) trials that reported mean changes and their standard deviation (SD) for each negative symptom dimension throughout the trial for both the intervention and control groups, or provided the necessary information for effect size calculation.If data were unreported, the corresponding author was contacted via email to request necessary information.If more than one published article used a single dataset, the most comprehensive article was included.

| Data extraction
The following data were extracted from included papers: first author, publication year, population, intervention, comparison, outcome, study design, country, and funding source(s) (Table 1).

| Statistical analysis
This meta-analysis was conducted using Stata 15 (Stat Corp., College Station, Texas, USA).Scale differences between pre-and posttreatment (mean and SD) in the intervention and sham groups were used to calculate the overall effect sizes.If SD values for the mean change were unavailable and the correlation coefficients were unreported, post-treatment scores and SD were used in accordance with the Cochrane Handbook for Systematic Review of Intervention guidelines (http:// www.cochr ane-handb ook.org).Standardized mean differences (SMD) for each study were calculated for analyses.
A total SMD was calculated for each negative symptom dimension.
Positive SMDs were interpreted as indicating a favorable effect of sham stimulation, while negative SMDs were interpreted as indicating a favorable effect of active stimulation.To obtain overall effect sizes, we applied a random-effects model that took study heterogeneity into account.We used chi-square to assess the heterogeneity of the data.Two-sided 95% confidence intervals (CI) were used to assess significance.Funnel plots and Egger regression were used to evaluate potential publication bias.Sensitivity analysis was examined using the Rosenthal fail-safe N-test. 31The fail-safe number is computed as the number of studies with an average sample size and nonsignificant outcomes that are needed in order for the effect size of the meta-analysis to reach nonsignificance.Upon identifying substantial heterogeneity, we conducted subgroup analyses using a random-effects model.We used the Physiotherapy Evidence Database (PEDro) scale to report quality assessment (Table S3).The PEDro scale consists of Intention-to-treat analysis; (10) Between-group statistical comparisons; and (11) Reporting of point measures and measures of variability. 32We followed the Cochrane Handbook for GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) for quality assessment.We use the GRADEpro GDT (https:// grade pro.org/ ) online platform to evaluate the evidence quality of the results and manually create an evidence summary table.

| RE SULTS
A total of 224 articles were considered for a full-text review, and eight articles were included in the meta-analysis (Figure 1).The primary outcomes of meta-analyses showed significant effects of NIBS on general negative symptoms and five dimensions.Among the five dimensions, better improvement effects were found on avolition and anhedonia.The secondary outcome was a subgroup analysis of the included studies based on stimulation frequency and total sessions.[28][29][33][34][35] The participant characteristics and NIBS parameters for each included study are in Table 1.A cumulative sample of 431 patients with schizophrenia was included across all studies.Their mean age was 38.15 ± 11.38 years, and the mean (range) proportion of male participants was 66.59% (48%-100%).All included RCTs allowed concurrent treatment with antipsychotics during the study period.][28]35 Quality assessment details are summarized in Table S3.Based on the PEDro scores, we found no concerns regarding the quality of the included studies and the subsequent results.

| Primary outcomes
The overall effects of NIBS efficacy on the negative symptoms of schizophrenia were statistically significant (Figure 2A

| Secondary outcome
Subgroup analysis was conducted based on stimulation frequency (once or twice daily) and total sessions (10 or >10).Subgroup analysis of studies with the lower stimulation frequency (once daily) revealed a significant difference in therapeutic effects be- ).Of note, the effects for this group (once daily) are higher than the general findings.However, studies with the higher stimulation frequency (twice daily) did not show a significant difference between active and sham groups on either the total score or any subscale score (Figure 3A-F).
Subgroup analysis of studies that administered >10 sessions revealed a significant difference in therapeutic effects between

| GRADE system recommendation grading
This meta-analysis had six main outcomes: NIBS impacts on general negative symptoms and each of five dimensions (affect flattening, alogia, attention impairment, anhedonia, and avolition) among patients with schizophrenia.The GRADE system-based recommended grading for each outcome is presented in Table S4.Among them, four outcomes are considered of low quality, and two results are of moderate quality.

| DISCUSSION
Significant recent progress has been made regarding the effectiveness of for treating patients with schizophrenia, as evidenced by findings from basic and clinical studies.Several meta-analyses have consistently demonstrated the positive therapeutic effects of NIBS on the negative symptoms of schizophrenia. 7,9,10,36However, these studies are limited insofar as they often treat negative symptoms as a homogeneous construct, neglecting the diverse dimensions and unique characteristics within symptom domains.Herein, we summarized the impact of NIBS on negative symptoms, including five specific dimensions, to supplement the existing research.
The results of this meta-analysis show that NIBS has different effects across the negative symptom dimensions.According to SMD interpretations (<0.4 is a small effect size, 0.4-0.7 is a moderate effect size, and >0.7 is a large effect size), NIBS intervention has a moderate effect size on improving avolition (SMD = −0.47)and anhedonia (SMD = −0.63),and a small but statistically significant effect on affect flattening (SMD = −0.39),attention impairment (SMD = −0.33),and alogia (SMD = −0.32).From the perspective of neural mechanisms, growing evidence shows that anhedonia and avolition are linked, and that both may derive from deficient reward network functioning. 11Further analysis of the neuroimaging findings in patients with schizophrenia has shown that brain regions related to anhedonia and avolition overlap with reward networks, including the VS, ACC, and OFC. 37In the reward system, information is delivered from VS and OFC to ACC, where cost/benefit analysis is run.In turn, the ACC sends projections to the anterior VMPFC and DLPFC for ultimate decision-making. 37,38[41] Subgroup analysis indicated that >10 stimulation sessions are needed to reduce the negative symptoms of schizophrenia.The cumulative clinical effects of more sessions have also been reported in other rTMS and tDCS studies. 7In addition to avolition and anhedonia, affect flattening also showed a moderate effect in subgroup analysis but a small effect in the overall meta-analysis.Therefore, we assume that the number of sessions is important to the effects of NIBS on the negative symptoms of schizophrenia.To the extent possible, future studies should evaluate >10 NIBS sessions to ensure therapeutic effectiveness.
The subgroup analysis also showed that studies in which stimulation was administered once daily led to a significant therapeutic difference between active and sham groups.In a five-day study, tDCS induced greater increases in motor evoked potential amplitude when administered once daily compared with twice daily, consistent with the finding herein. 42In contrast, a subgroup analysis of studies administering NIBS more often than once daily revealed a significant difference in therapeutic effects between active tDCS and sham. 10Because only two studies fell into the twice-daily stimulation category, this finding may not be robust.Though current trials investigating the therapeutic value of neuroplasticity-inducing NIBS typically use a protocol of once daily administration for 1-2 weeks, there is no direct scientific evidence to support this as a best practice. 43Indeed, some researchers have asserted that this stimulation frequency is used for practical or convenience-based reasons. 44Overall, more experimental data are needed to further refine the optimal parameters for NIBS treatment effects.
Several limitations of this systematic review and metaanalysis should be noted.First, it was based on only eight studies, because few available studies include SANS subscale scores.
We contacted corresponding authors by email whenever possi- or providing effect sizes whenever possible, to facilitate their contributions to future meta-analyses.Although the number of included studies was relatively small, our results are nonetheless meaningful; on the basis of this evidence, future NIBS interventions can be tailored to individual patients' symptom profiles, with protocols determined by their specific symptom dimensions.
Second, only the effects of stimulation frequency and number of sessions were considered.However, in the Table 1 summary, we note that the included studies also differ by region, population, center setting, and other aspects that may affect treatment effectiveness.However, those data were insufficient for further subgroup analyses.The optimal NIBS parameters have yet to be determined.More research and additional, original data will be conducive to developing and standardizing a treatment manual and promoting the development of this technology.Third, the long-term effects of NIBS were not explored herein because of variations in durations between the last stimulation visit and follow-up, which either varied across studies or were unreported.
Finally, although we searched the gray literature library, we were unable to avoid all deviations.According to GRADE, our evidence levels are low-to-moderate quality and thus require careful interpretation.
F I G U R E 2 Forest plots of the results of the meta-analyses.
This systematic review and meta-analysis show that there are significant effects of NIBS on general negative symptoms and on all five specific domains.Among the latter, there are more pronounced improvement effects on avolition and anhedonia.These cumulative results suggest that once daily and than 10 stimulation sessions are likely needed to improve negative symptoms in patients with 11 items encompassing external validity (item 1), internal validity (items 2-9), and statistical reporting (items 10 and 11): (1) Eligibility criteria and source; (2) Random allocation; (3) Concealed allocation; (4) Baseline comparability; (5) Subjects blinded; (6) Therapists blinded; (7) Raters blinded; (8) Adequate follow-up (>85%); (9)

| 5 of 11 CHEN
et al. a significant difference between the active and sham groups on either total score or any subscale score (Figure 4A-F).

F I G U R E 3 | 9 of 11 CHEN
Forest plots of the results of the subgroup analysis (based on frequency).et al. schizophrenia.Guidance standards on NIBS stimulation treatment parameters are needed for future research and clinical treatments.AUTH O R CO NTR I B UTI O N S Conceptualization, Laiquan Zou; references selection and data extraction, Yuying Chen and Zhuofeng Li; meta-analysis and original draft, Yuying Chen; review and editing, Chao Yan and Laiquan Zou.All authors have read and agreed to the published version of the manuscript.
The first row for each study represents the active group and the second row represents the sham group.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of included/excluded studies.
ble, but ultimately had to exclude studies that did not provide sufficient data.Researchers should consider including raw dataF I G U R E 1